A variety of biomedical sensors are routinely used by physicians or clinicians to monitor physiological variables such as respiratory rate, blood pressure, and temperature. A relatively new addition to the repertoire of biomedical sensors is the enzyme electrode. This is a sensor that combines certain analytical enzymatic techniques with commonly used chemical-selective electrodes. Enzyme electrodes enable the user to determine the concentration of certain biochemicals rapidly and with considerable accuracy. Currently there are enzyme electrodes that can detect urea, uric acid, glucose, various alcohols, and a number of amino acids when used in certain well-defined situations.
Of the available enzyme electrodes, perhaps the one that is most widely used is the glucose electrode, of which there exist several variations. The first report that enzymes could be used to measure glucose was that of Clark in U.S. Pat. No. 3,539,455. They proposed that glucose could be detected amperometrically using the enzyme glucose oxidase held between two membranes surrounding an oxygen or hydrogen peroxide electrode. As glucose and oxygen diffuse through the membrane, there was a reduction in oxygen concentration proportional to the concentration of glucose in the sample fluid as a result of the enzymatic process described below. ##STR1##
The electrode can be polarized cathodically to detect residual oxygen not consumed by the enzymatic proess or polarized anodically to detect the product of the enzyme reaction, hydrogen peroxide.
The glucose enzyme electrode was apparently first put into practice by Hicks et al. as described in U.S. Pat. No. 3,542,662. These inventors employed two oxygen electrodes, unlike the single electrode design of Clark, and immobilized glucose oxidase on one of them. A dual enzyme electrode configuration, where one electrode had immobilized enzyme, was intended to be insensitive to changes in oxygen levels not mediated through glucose oxidase. Glucose oxidase was immobilized by entrapment in a polyacrylamide gel matrix over one of the oxygen electrodes. Since this electrode was still sensitive to changes in oxygen tension, the difference between the output of the two oxygen electrodes was recorded to reflect glucose concentrations that were relatively independent of fluctuations in background oxygen concentration.
Additional changes in the overall design of the basic oxygen sensor as they relate to modifications in the enzyme membrane surrounding the sensor or to modifications in the electrodes are described in U.S. Pat. Nos. 4,356,074; 4,073,713; 1,442,303; 3,948,745; and 3,847,777, respectively. None of these modified enzyme oxygen sensing electrodes can be used to monitor in vivo levels of various enzyme substrates or their byproducts.
It is desirable to have enzyme electrodes that can be implanted in patients to continuously monitor blood or tissue fluid concentrations. For instance, it is particularly desirable to have an implantable enzyme electrode sensor for use in diabetics, to continuously monitor glucose concentrations. While there exist a number of oxidase-based enzyme electrodes capable of detecting glucose or other substances such as alcohol and uric acid in vitro because of design features associated with these sensors, they are not suitable for use to detect these substances in vivo.